November 2011

Experts stress selectivity in advanced ulcer care

Despite the expense associated with advanced wound care technologies, evidence suggests that switching from standard care makes both clinical and economic sense if a diabetic foot ulcer has not experienced a 50 percent reduction in wound area after four weeks.

By Emily Delzell

Many practitioners still think of advanced wound care technologies for diabetic foot ulcerations as cost-prohibitive treatments of last resort. Yet, when used at the right time for the right patients, advanced care can lower the human and economic costs of potentially devastating wounds.

In the late 1990s a systematic literature review of quality of DFU care in the U.S. found that 30% to 40% of patients were not being treated according to evidence-based guidelines and that 20% to 30% of DFU care was inappropriate, unnecessary, or potentially dangerous.1 More recent reports provided definitive data on predictors of failure to heal and of successful healing2,3 and the efficacy of certain adjuvant (advanced) therapies.4 The Wound Healing Society published guidelines on treatment of lower extremity ulcers in 2006,5 updating them in 2008.6

With these issues in mind, a consensus panel of multidisciplinary experts convened to review the evidence for and feasibility of a number of modalities for DFU care.

The panel, which published its findings in 2010 in Ostomy Wound Management,7 concluded that when wounds heal too slowly, clinicians should move to advanced wound care to accelerate healing and decrease complications. Slow healing was defined per the earlier findings of Sheehan et al2 as less than a 50% reduction in the wound area four weeks from baseline. The panel recommended that advanced wound care be considered the new standard of care for such wounds rather than a “last resort” and further noted that, for some patients, even earlier intervention is warranted.

Figure 1. A 38-year-old man with diabetes-related blindness and a foot ulcer that had been treated for eight months before he was referred for advanced care. His wound healed in two months with six applications of Dermagraft. (Provided by James Stavosky, DPM.)

“In our center we generally follow the guideline established by Peter Sheehan and colleagues, switching to advanced care when patients don’t achieve 50 percent healing at four weeks,” Rogers said. “Bioengineered tissues and other advanced modalities are great additions to the clinic setting; they don’t require use of an operating room or of anesthesia and do not, as many assume, increase economic costs.”

Advanced care also reduces morbidity and mortality in patients with slow-healing wounds.

“Well-done studies have shown that if you continue to provide the same management to slow-healing wounds, you’re wasting time, and if you waste time with patients with diabetic foot ulcers you’re putting them at risk for soft tissue infection, bone infection, amputation, and subsequent mortality,” said Robert S. Kirsner, MD, PhD, panel member and professor, vice chair, and Stiefel Laboratories Chair in the Department of Dermatology and Cutaneous Surgery at University of Miami Hospital.

Decision-making

A surprisingly high number of DFU patients fail to heal with standard care. Margolis et al evaluated the rate of neuropathic ulcer healing through a meta-analysis of 10 control groups from prospective clinical trials.8 Control groups used good wound care, which included debridement, offloading, and either saline-moistened gauze or placebo gel and gauze. Of the 622 patients assessed (172 in the 20-week end point group and 450 in the 12-week end point group), complete wound closure occurred in 24% of patients at 12 weeks and in only 30.9% at 20 weeks.8

There are a number of ways to predict wound healing, Kirsner noted. These include assessment of the wound’s baseline characteristics, such as its area, duration, and stage. There are two major systems for wound classification: the Wagner system and the University of Texas system.

The Wagner system assesses ulcer depth and the presence of osteomyelitis or gangrene with scores of zero to five. The University of Texas system uses a matrix of grades (0 to 3) and scales (A to D) to assess ulcer depth and to detect the presence of infection and lower extremity ischemia.9

“Wagner is important because criteria for approval for some things such as hyperbaric oxygen therapy is based on this system. But the University of Texas classification is probably superior because it incorporates vascular disease into the staging and thus has a more refined predictive ability,” Kirsner said.

A 2001 study published in Diabetes Care applied the two systems to 194 patients with new DFUs to compare their utility as predictors of clinical outcome. Healing times did not differ significantly between the Wagner and University of Texas systems, but there was a significant stepwise increase in healing time with each stage of the University of Texas system (p<0.05), and stage predicted healing (p<0.05).9

The authors concluded that the University of Texas system’s combination of grade and stage provides a more comprehensive picture of DFUs than the Wagner system, which has limited ability to identify and classify infected or dysvascular wounds.

The 2010 consensus panel also favored the University of Texas system as a predictor of clinical outcomes, though they noted the Wagner system is more widely used and may, in some instances, be required for reimbursement.

Kirsner noted that, in practical terms, “Using the 50 percent reduction at four weeks measure is a convenient method for measuring progress in clinical settings. Failure to reach this mark accurately identifies most patients who need advanced therapies.”

Sheehan’s 2003 multicenter prospective study of 203 DFU patients assessed the percent area reduction (PAR) at four weeks for each ulcer. The median four-week PAR between ulcers healed at 12 weeks and those not healed at 12 weeks was 53%.

More than half (58%) of patients with four-week PARs above the midpoint had full ulcer healing at week 12. In contrast, only 9% of those patients whose four-week PAR was less than the median were fully healed at week 12.

The absolute change in ulcer area at four weeks was significantly greater in healers versus nonhealers (1.5 cm2 vs 0.8 cm2, p<0.02): The PAR at four weeks in those who healed was 82% (95% Cl 70-94) and 25% (p<0.001) in those who failed to heal.2

Synder et al also found that PAR was a robust predictor of healing likelihood. In a 2010 post hoc analysis of control participant data from two previous randomized controlled trials (total, 250 patients), investigators found that a 50% PAR at four weeks was significantly associated with healing at 12 weeks independent of baseline ulcer area (p<0.001).10

Further, the investigators showed that PAR had predictive value as early as two weeks from baseline. Approximately one-tenth or fewer of DFUs with a PAR <50% at weeks two, three, or four were healed by week 12 (12%, 9%, and 4%, respectively) while more than half of DFUs with at least 50% PAR at weeks two, three, or four healed by week 12 (58%, 55%, and 54%, respectively).10

Although the 2010 consensus panel validated these parameters and strongly recommended their broad adoption as indicators for moving patients from standard to advanced care, neither these measures nor adjuvant therapies are being utilized at appropriate levels in many clinics and practices in the U.S., said James W. Stavosky, DPM, coauthor of the post hoc analysis, chief of podiatric surgery, Seton Medical Center, Dale City, CA, and a wound care specialist at the San Francisco Center for Advanced Wound Care.

“I’d say only about five percent of patients are receiving treatment with advanced products, and that should be closer to 40 or 50 percent,” Stavosky said. “Almost 900,000 individuals develop diabetic foot ulcers each year, and studies estimate about 336,000 of these are slow healers,11-13 but few receive anything beyond standard care.”

Figure 2. A 37-year-old woman with diabetes who presented at an emergency department. Large amounts of pus were drained from the wound, followed by removal of infected tissue, wound closure, negative pressure wound therapy, and application of living skin equivalents. (Provided by James Stavosky, DPM.)

At the San Francisco Center for Advanced Wound Care, increasing the use of advanced products has decreased healing times by almost two weeks, according to Stavosky. He noted that in 2006, 322 new DFU patients received 59 applications of advanced products in 2790 clinical encounters; the 360 new DFU patients in 2010 received 414 applications of such products in 3730 encounters. Healing times in 2006 averaged 54 days, but by 2010 that figure had decreased to 42 days. Healing rates rose from 96% in 2006 to 98.9% in 2010.

Advanced care options and costs

In a 2007 review of treatment strategies for DFUs, Armstrong et al concluded that active therapies such as bioengineered skin substitutes can promote healing in wounds that fail to meet the 50% PAR mark at four weeks.14

Only three such products have met Food and Drug Administration (FDA) standards for premarket approval (PMA) status, which require evidence from randomized controlled trials of efficacy in speeding DFU healing. Two are living skin equivalents: Dermagraft, a cryopreserved human fibroblast-derived dermal substitute, and the bilayered skin substitute Apligraf. The third is Regranex, a topical gel containing recombinant human platelet-derived growth factor. The trials of these products involved well-perfused, uninfected partial-to-full thickness wounds.15-18

“These products are all very easy to apply,” Kirsner said. “The learning curve is less about their application and more about subsequent management—understanding how the wound should look during the healing process. These products stimulate drainage and tend to ‘melt’ into the wound. They can cause a wound to look infected when it’s not, and this can sometimes lead less experienced practitioners to remove the product before it has had a chance to do its work.”

Stavosky also noted that billing for advanced products can involve some reimbursement challenges.

“These are costly products and practitioners may be apprehensive about the initial outlay when reimbursement seems questionable,” he said. “Living skin equivalents, for example, cost about $1500 a piece, and the typical diabetic foot ulcer patient needs four and a half pieces. But the manufacturers offer good training in billing and coding issues as well as in application and management.”

The use of these products, however, is not more expensive than subjecting patients to prolonged and potentially harmful treatment with standard care when such care is failing to heal the wound, he said.

A recent study conducted by a health policy analysis group mined Medicare and private insurer data to compare the costs and effects of treating DFUs with advanced and conventional care.19 Study authors used a computer model to simulate health status over 52 weeks in a cohort of 10,000 patients who had a DFU treated with either a human fibroblast-derived dermal substitute (HFDS) plus standard care or with standard care alone. This method allowed investigators to evaluate the long-term economic and clinical effects of DFU care.

Weekly health state transition probabilities were derived from a 12-week randomized controlled trial that compared the efficacy of DFU treatment with HFDS plus standard care or standard care alone.16 In that trial, wound dressings consisted of wet-to-dry gauze; participants underwent sharp surgical debridement of necrotic or hyperkeratinized tissue at their initial visit and on a as-needed basis at follow-up visits; patients, who were ambulatory for an average of eight hours per day, wore diabetic footwear with custom inserts or healing sandals to offload their wounds; and individuals in the HFDS plus standard care group could receive treatment with HFDS on a weekly basis during weeks one through eight if ulcers were unhealed but not infected.

In the cost-effectiveness analysis, HFDS plus standard care healed more ulcers than standard care alone (76% vs 50%) and individuals receiving advanced plus standard care had fewer amputations (12% vs 32%). The average estimated cost to Medicare for each healed ulcer was $30,344 for standard plus advanced care and $56,516 for standard care alone. Although advanced care costs to Medicare were higher in the first six months of care, they were lower after this period. Private insurers achieved cost neutrality at eight months.

“Bioengineered tissue products provide several advantages: they are biologically active, provide potent delivery of growth factors, which achieve their effects their effects by binding to specific cellular receptors, glycosaminoglycan and matrix and provide protection for exposed viable structures,” Stavosky said. “In addition to slow-healing foot ulcers of any size, clinicians should consider their use in patients with complex issues and those who have exposed dysvascular structures or who aren’t good candidates for surgery.”

All the experts interviewed for this article stressed that advanced care technologies are not a panacea and that good standard wound care is an absolute must.

“In the clinical management of any type of wound, especially chronic wounds, a number of issues must be covered, including evaluation. You’ve got to understand the etiology and perform all the basics because advanced products alone can’t give success,” Stavosky said. “Basics that shouldn’t be missed but sometimes are include the need for infection control, sharp debridement, maintaining a moist wound environment, appropriate offloading or compression therapy, and maintaining an adequate nutritional status of the patient. Collectively addressing these issues can be considered the foundation of good wound care.”

Kirsner also noted that good standard care, primarily adequate and early offloading, is the key consideration for practitioners treating patients with DFUs.

“The earlier wounds are detected, the better. Offloading is difficult to enforce, but it’s the most important thing you can do for patients,” he said. “In addition, monitoring patients’ progress is critical—if patients fail to improve in a short time, you must change your treatment strategy.”

Rogers also emphasized offloading, as well as regular debridement, as essential for ulcer healing.

“If wounds don’t respond adequately to these measures in four weeks, then an aggressive initial debridement, followed by negative pressure wound therapy, followed by the use of bioengineered tissue or surgical skin closure seems to offer the best chance of success,” Rogers said.

Not all patients who receive advanced therapies will heal, Kirsner noted.

“However, if you treat individuals appropriately and promptly, up to 70% can achieve wound closure,” he said.

Although Stavosky and his patients are reaping the benefits of advanced wound care in terms of shorter healing times and the salvation of limbs and lives, he finds the rigidity of PMA-mandated indications for advanced wound care products frustrating.

“These products are approved for very specific indications. All wounds tend to heal in a similar fashion and we as clinicians should be able to make decisions about the use of advanced products rather than being locked into approved indications,” he said. “It costs companies so much to go through the rigorous clinical trial process that it’s prohibitive for many of them, and our patients are the ones losing out. Sometimes third party insurers will reimburse for advanced products used off label, but Medicare won’t.”

References

1. Schuster MA, McGlynn EA, Brook RH. How good is the quality of care in the United States? Milbank Q 1998;76;517-563. Available at http://www.jstor.org/pss/3350511. Accessed October 21, 2011.

2. Sheehan P, Jones, P, Caselli A, et al. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial.Diabetes Care 2003;26(6):1879-1882.

11. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.

19. Zhang Y, Hogan H. Cost effectiveness of a human fibroblast-derived dermal substitute for the treatment of diabetic foot ulcers in Medicare and commercially insured populations. Presented at the 71st Scientific Session of the American Diabetes Association, San Diego, CA, June 2011.